We propose to continue our prospective investigation of determinants of non-insulin-dependent diabetes mellitus (NIDDM) with particular attention to physical activity, body fat distribution (waist:hip ratio), and diet, as well as to assess the role of these variables in modifying the risk of cardiovascular disease (CVD) among women with NIDDM. The proposed investigations to explore risk factors for NIDDM and its CVD complications in women takes advantage of the ongoing large prospective cohort study of 121,700 registered nurses currently aged 47-72 years. At entry in 1976, 2184 prevalent cases of diabetes were reported. Subsequently, from 1976-1990, approximately 3480 incident cases of diabetes have been reported and 2868 have been confirmed as NIDDM (5204 confirmed incident cases projected for 1976-96). The proposed study will continued to document and classify new diagnoses of NIDDM in this cohort. Questionnaire data have been obtained on a large number of exposures, including physical activity, anthropometric measures (waist and hip circumferences), family history of diabetes, and diet. Stratified and multivariate techniques will be used to quantitate the risk of NIDDM with different levels of physical activity, waist:hip ratio (WHR), and nutrient intake, after controlling for potentially important confounding variables. Modifiable determinants of WHR and weight gain in adulthood also will be examined. In addition, in a companion application, we propose to assess the role of fasting hyperinsulinemia as a predictor of subsequent diagnosis of NIDDM in nondiabetic women, as well as a predictor of CVD events among nondiabetic women and among diabetic women without prior hypoglycemic therapy. Further their role of glycemic control as a determinant of CVD in diabetic and nondiabetic women would be assessed, as well as the role of polymorphism of the glycogen synthase gene as a genetic marker for NIDDM. These analyses of biochemical markers would be conducted wit a "nested" case control design, utilizing blood specimens collected on more than 33,000 participants in 1989-90. The large size of the cohort, the prospective design, the high follow-up rate (>92%), the detailed exposure data, and the availability of blood specimens make this cohort a unique resource to test several etiologic hypotheses related to NIDDM. Our proposed five-year renewal assumes the renewal, in three years, of the MERIT award funding of the overall Nurses' Health Study (CA 40356).